Muscle loss or "atrophy" occurs as the result of a number of disparate conditions including: aging, immobilization/bedrest, metabolic diseases, cancer and neurodegenerative diseases. To date, there are no effective pharmacologic agents to prevent or treat the loss of muscle mass or strength, or to accelerate muscle recovery following atrophy. The pathways involved in controlling anabolic and catabolic processes in muscle are poorly defined, consequently there are few potential targets for drug development. Recent data, however, suggests that the novel, muscle specific E3 ubiquitin ligases, MuRF1 and MAFbx/Atrogin-1, are critical regulators of the atrophy process. Both genes are up-regulated in all acute atrophy models tested to date, suggesting similar transcriptional control. In this proposal, the MuRF-1 and MAFbx promoters will be functionally characterized in cultured cells and in skeletal muscles in vivo, with particular attention to the interaction between consensus GRE and FOXO sequences. Our data will provide critical information about the transcriptional control of these genes leading to means to control their expression under conditions that induce muscle loss.